Organogenesis of the heart is a complex process requiring multiple morphogenetic events. As inborn errors in this process are frequent, congenital heart disease (CHD) represents the most common cause of human birth defects and the most common non-infectious cause of death in children. Despite rapid recent advances in the diagnosis and surgical treatment of CHD, little is known about the genes that control cardiac morphogenesis. The long-term objective of this work is to identify, isolate, and characterize the role of genes involved in cardiac morphogenesis and analyze their contribution to human CHD. A prospective (forward) genetic screen is proposed to directly identify mice bearing mutations in genes required for cardiac morphogenesis. A screening strategy based on the transition from fetal to neonatal circulation has been established. A pilot screen has been performed, and two independent lines with distinct heritable cardiovascular morphogenesis defects have been identified. An ongoing large-scale forward genetic screen will be expanded to identify genes involved in cardiac morphogenesis. In Specific Aim 1, chemically mutagenized mice will be screened to identify mutant mice with defects in cardiac morphogenesis. In Specific Aim 2, the mutations of interest will be mapped. In Specific Aim 3, a subset of mutations will be characterized to molecularly identify the responsible gene. The principal investigator is an M.D., Ph.D. with a doctoral degree in Biochemistry, residency training in Anatomic Pathology, and fellowship training in Congenital Cardiac Pathology. The proposed training program includes training in cardiac development, molecular genetics and positional cloning under the mentorship of Dr. Jonathan G. Seidman, whose lab studies the genetics of cardiovascular disease. The candidate will combine clinical expertise with research training to pursue a career as a clinician-scientist in the field of cardiovascular morphogenesis and congenital heart disease.